Guanosine monophosphate reductase (GMPR) catalyzes the NADPH dependent reductive deamination of GMP to inosine monophosphate (IMP). GMPR is a member of the “salvage pathway” in nucleotide biosynthesis which serves to recycle nucleotides and bases back into biosynthetic pathways leading to the synthesis of ATP and GTP. ATP and GTP are the principle purine nucleotide precursors to DNA and RNA in cells, and they control various aspects of signal transduction and energy metabolism. IMP dehydrogenase (IMPD) is a key enzyme at the branch point in the biosynthetic pathway leading to the synthesis of both ATP and GTP. Therefore, by regulating the substrate pools of GMP and IMP, GMPR participates in the regulation of both ATP and GTP.
GMPR occurs in most organisms including man. The human GMPR is a tetrameric molecule estimated to be approximately 170 KDa in size that is made up of monomers of approximately 37 KDa. Several variant alleles of the human GMPR gene have been found in the chromosome 6-linked locus of the gene. The N-terminal 54 amino acid sequence of GMPR is found to be virtually identical to that of the major subunit of another chromosome 6-linked gene, glucose-6-phosphate dehydrogenase (G6PD; Kanno, H. et al. (1989) Cell 58: 595–606). However, the catalytic activity of GMPR is found in the C-terminal portion of the molecule and differs significantly from that of the latter enzyme.
Inhibitors of purine nucleotide biosynthesis in general, and of GTP synthesis in particular, have long been employed as antiproliferative agents to treat cancer and viral diseases. The antitumor agents, tiazofurin and 3-deazaguanosine, originally thought to act through inhibition of IMPD have subsequently been found to be inhibitors of GMPR as well (Streeter, D. G. and Robins, R. K. (1983) Biochem. Biophys. Res. Comm. 115(2): 544–50; Page, T. et al. (1985) Cancer Chemother. Pharmacol. 15: 59–62; Prajda, N. et al. (1993) Cancer Res. 53: 5982–6). Antiviral agents such as the antibiotic mycophenolic acid also target this portion of the purine biosynthetic pathway (Franklin, T. J. and Cook, J. M. (1969) Biochem. J. 113: 515–24).
The discovery of polynucleotides encoding guanosine monophosphate reductase, and the molecules themselves, provides a means to investigate the role of the enzyme in cell replication and cell proliferation and in diseases associated with these processes. Such molecules related to guanosine monophosphate reductase satisfy a need in the art by providing new diagnostic or therapeutic compositions useful in diagnosing and treating cancer, viral diseases, inflammatory diseases, and immunological disorders.